Transcription Factor T-bet in B Cells Modulates Germinal Center Polarization and Antibody Affinity Maturation in Response to Malaria
Ann Ly,
Yang Liao,
Halina Pietrzak,
Lisa J. Ioannidis,
Tom Sidwell,
Renee Gloury,
Marcel Doerflinger,
Tony Triglia,
Raymond Z. Qin,
Joanna R. Groom,
Gabrielle T. Belz,
Kim L. Good-Jacobson,
Wei Shi,
Axel Kallies,
Diana S. Hansen
Affiliations
Ann Ly
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia
Yang Liao
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia
Halina Pietrzak
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia
Lisa J. Ioannidis
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia
Tom Sidwell
The University of Melbourne, Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, 792 Elizabeth Street, Melbourne, Victoria 3000, Australia
Renee Gloury
The University of Melbourne, Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, 792 Elizabeth Street, Melbourne, Victoria 3000, Australia
Marcel Doerflinger
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia
Tony Triglia
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia
Raymond Z. Qin
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia
Joanna R. Groom
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia
Gabrielle T. Belz
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia
Kim L. Good-Jacobson
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia; Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
Wei Shi
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia; Department of Computing and Information Systems, The University of Melbourne, Parkville, Victoria 3010, Australia
Axel Kallies
The University of Melbourne, Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, 792 Elizabeth Street, Melbourne, Victoria 3000, Australia; Corresponding author
Diana S. Hansen
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia; Corresponding author
Summary: Despite the key role that antibodies play in protection, the cellular processes mediating the acquisition of humoral immunity against malaria are not fully understood. Using an infection model of severe malaria, we find that germinal center (GC) B cells upregulate the transcription factor T-bet during infection. Molecular and cellular analyses reveal that T-bet in B cells is required not only for IgG2c switching but also favors commitment of B cells to the dark zone of the GC. T-bet was found to regulate the expression of Rgs13 and CXCR3, both of which contribute to the impaired GC polarization observed in the absence of T-bet, resulting in reduced IghV gene mutations and lower antibody avidity. These results demonstrate that T-bet modulates GC dynamics, thereby promoting the differentiation of B cells with increased affinity for antigen. : Antibody responses play a pivotal role in clinical immunity to malaria. Ly et al. report that that germinal center (GC) B cells upregulate the transcription factor T-bet during infection. T-bet favors commitment of B cells to the GC dark zone, thereby augmenting immunoglobulin gene mutation rates and antibody affinity maturation. Keywords: malaria, T-bet, B cells, germinal center, antibodies, affinity maturation
